Surgery and postoperative radiotherapy affect the prognosis of esophageal cancer: A SEER analysis

The principal treatment modalities for esophageal cancer are radiation, chemotherapy and surgery or a combination of them. In some sense, technological advances have tremendously heightened patients’ survival rates. Nevertheless, the debate on the prognostic value of postoperative radiotherapy (PORT) has never ceased. On that account, this study made an effort to probe deep into the effects of PORT and surgery on the prognosis of stage III esophageal cancer. Our study included patients diagnosed with stage III esophageal cancer between 2004 and 2015 through the Surveillance, Epidemiology, and End Results (SEER) program. We performed propensity score matching (PSM) on the basis of whether surgery was carried out and whether PORT conducted. We identified the independent risk factors by multivariate Cox regression and constructed a nomogram model. In this research, we included 3940 patients, and the median follow-up is 14 months: 1932 cases without surgery; 2008 cases with surgery, and 322 cases of them underwent PORT. In the postPSM patient cohort, patients who underwent surgery had a median overall survival rate (OS) of 19.0 (95% confidence interval [CI] 17.2–20.8) and a median cancer-specific survival rate (CSS) of 23.0 (95% CI 20.6–25.3) months, which were remarkably higher than those without surgery (P < .001). The OS（P < .05）and CSS（P < .05）of the patients who underwent PORT were lower than those who did not. Similar results were obtained in the groups of N0 and N1. This study revealed surgery can heighten patients’ survival rate, while PORT could not elevate patients’ survival rate in stage III esophageal cancer patients.


Introduction
As the 10th most common cancer worldwide, 604,100 (3.1%) new esophageal cancer cases and 544,076 (5.5%) esophageal cancer deaths were reported in 2020. [1] The first choice method of treatment for patients with resectable stage III esophageal cancer is surgery. Nevertheless, survival rate for patients who underwent surgery alone was far from satisfactory. [2][3][4] {Smyth, 2017 #3} Symptoms of stenosis may not appear until the tumor reaches a relatively advanced or even locally metastatic stage. [3,5] Endoscopic resection is feasible in the early stage, chemotherapy can be considered in the advanced stage, and chemotherapy, radiochemotherapy, surgery and combined therapy are recommended in the middle. Surgery alone is less effective and prone to recurrence, therefore needs to be combined with a variety of other adjuvant treatments. [6][7][8] Postoperative radiotherapy (PORT) is one of the extensively used methods. PORT has been employed in the treatment of esophageal cancer since 1969. [9] Nonetheless, some studies have reported conflicting results regarding the role of PORT. [10][11][12] Just as evidently indicated by the results of a randomized controlled trial, PORT elevated patients' survival rate in stage III esophageal cancer compared with a control group (P = .0027). [10] In contrast, in another randomized controlled trial, esophageal cancer patients who underwent PORT had markedly shorter survival rate times than nonPORT patients (P = .02). [11] A meta-analysis on 3 randomized controlled trials and 7 retrospective studies persuasively illustrates that PORT can ameliorate overall survival rate (OS) (P = .0004) and disease-free survival rate (P = .004) in esophageal cancer compared with surgery alone. [12] These studies demonstrates that the role of PORT in esophageal cancer still remains controversial. As The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. Medicine a consequence, it remains of interest to evaluate the prognostic value of surgery and PORT. By comparing the role of surgery and PORT, providing clear evidence for the clinical decision-making of clinicians was our primary aim in conducting this study.

Study population
Surveillance, Epidemiology, and End Results (SEER) 18 Regs custom Data (1975Data ( -2016 is the data source for this retrospective study. We identified patients diagnosed stage III esophageal cancer from 2004 to 2015 (Fig. 1). Patients included in this exploration had to meet all of the criteria over 18 years of age, tumor size <600 mm, diagnosed with stage III esophageal cancer. The exclusion criteria were as follows not first malignant primary indicator, complete data could not be obtained, patients diagnosed by autopsy. We extracted the following data from the SEER database: age, primary site of tumor, histologic, race, gender, chemotherapy history, T stage, N stage, surgery history, radiation history, tumor size, marital status, radiation sequence with surgery, and follow-up information. We employed OS and cancer-specific survival rate (CSS) as survival rate times analyzed in this investigation. OS is the survival rate time from the day of diagnosis to the day of death from any cause or last follow-up. CSS is an OS measure excluding other causes of death. In this research, we adopted the AJCC 6th edition TNM staging. We use data from public databases and was exempt from institutional review board approval.

Nomogram construction
Univariate and multivariate Cox proportional hazards regression analyses were performed on the postpropensity score matching (postPSM) cohort. On the basis of the above results, we constructed a nomogram using R version 4.1.3.

Statistical analysis and the optimal cutoff value
We compared categorical variables using chi-square or Fisher's exact test. 1:1 PSM of surgery and PORT were performed separately to eliminate possible effects of other variables. The logrank test was adopted to evaluate Kaplan-Meier survival rate curves and reported hazard ratios (HR) with 95% confidence interval (CI). In accordance with the results of univariate analysis, we included factors with P < .05 into multivariate analysis. SPSS v26.0 (SPSS Inc) and GraphPad Prism v8.0.2 (GraphPad Software, Inc.) were used for Statistical analysis. The optimal cutoffs for tumor size and age were determined in line with X-tile v3.6.1 (Yale University). P < .05 was considered statistically significant. www.md-journal.com

Baseline characteristics
In this exploration, 3940 stage III esophageal cancer patients were screened from SEER database, of whom 51.0% (n = 2008) underwent surgery and 49.0% (n = 1932) did not. We then compared the clinical characteristics of patients before and after PSM in accordance with whether the PORT is carried out ( Table 2). Although most variables did not exhibit statistical differences between PORT(+) and PORT(−) (P > .05), we still performed PSM to remove potential effects of other variables. Table 3 displays the clinical characteristics of all stage III esophageal cancer in different N stages.

The role of surgery and PORT
The median follow-up in our study was 14 months (range 1-155).
During the follow-up period, 3158 cases (80.1%) died, including 2743 cases (69.6%) of esophageal cancer deaths. In the whole cohort, half of patients (n = 2008,51.0%) received surgery, and 16.0% (n = 322)of those undergoing surgery received PORT. In an effort to minimize the influence of other variables, we conducted 1:1 PSM analysis according to surgery or nonsurgery and whether Table 1 Characteristics of patients before and after PSM according to whether or not surgery.  . 2c and d).We also probed into pre-PSM population in line with surgery or nonsurgery and whether the PORT is carried out, found that The median OS and CSS were conspicuously better in patients undergoing surgery than those did not ( . 2g and h). Hence, our results demonstrated that surgery can augment patients' survival rate, whereas PORT did not heighten patients' survival rate and even decreased OS and CSS.

Univariate and multivariate analysis
Univariate and multivariate analyses were performed on the postPSM cohort in line with whether the surgery is performed.
Univariate analysis manifested that OS and CSS were markedly correlated with age, tumor size, chemotherapy, radiation, surgery, grade and marital status, gender, Primary site and T stage ( Table 4). The multivariate analysis on OS revealed that age, tumor size, chemotherapy, radiation, surgery, T stage, grade, gender, marital status independently affected OS ( Table 4). The multivariate analysis on CSS revealed that age, tumor size, chemotherapy, radiation, surgery, T stage, grade, gender, marital status and primary site independently affected CSS (Table 4).

Nomogram construction
The nomogram was constructed in accordance with the independent factors including age, tumor size, chemotherapy, radiation, surgery, T stage, grade, gender and marital status (Fig. 4).
In the nomogram, chemotherapy exerted the most conspicuous influence on prognosis, followed by surgery and grade.

Discussion
When investigating the data from the SEER database for stage III esophageal cancer diagnosed between 2004 and 2015, we found that surgery noticeably prolonged patients' survival rate time. Similarly, we also arrived at the same conclusion in N0 and N1 patients. Meanwhile, we found that radiotherapy can better the OS and CSS of patients, but PORT will not ameliorate patients' survival rate and even lower OS as well as CSS. The value of PORT in patients with esophageal cancer remains controversial.
In several studies of patients with PORT, reporting an improvement in the 5-year survival rate in stage III esophageal cancer, [10] noticeably heightened disease-free survival rate in patients with thoracic esophageal squamous cell carcinoma (P = .030), [13] an improvement in the 5-year OS (P < .001) [14] and an improvement in OS in lymph node-positive patients (P < .001). [15] Nonetheless, relevant studies also suggested that PORT did not confer any survival rate benefit compared to nonPORT. As conspicuously revealed by a prospective study, compared with the control group, PORT had shorter overall median survival rate. [11] In another prospective randomized controlled study, there was no statistically significant difference in survival rate between the PORT group and surgery alone. [16] Just as conspicuously illustrated by a meta-analysis on 13 retrospective studies and 6 randomized controlled trials, PORT can ameliorate the OS only in retrospective studies. [17] Nevertheless, most of the aforementioned studies did not stratify patients by stage or had insufficient data or did not take into account the influence of other factors. As a consequence, there may be errors  According to the results of univariate analysis, we included factors with P < .05 into multivariate analysis. We found that the independent factors including age, tumor size, chemotherapy, radiation, surgery, T stage, grade, gender and marital status. CI = confidence interval, PSM = propensity score matching. www.md-journal.com in the detection of the effect of PORT on stage III esophageal cancer. As a result, we conducted this PSM study and found that PORT did not ameliorate patients' survival rate and even decreased OS and CSS. We matched 318 patients who underwent surgery alone with 318 patients who underwent PORT in an attempt to eliminate the influence of other factors. Apart from that, we obtained similar results when we investigated patients with stage N1 in accordance with whether PORT or not. We did not investigate it due to the deficiency of enough data on patients with stage N0. To investigate whether radiotherapy was responsible for this unusual outcome or PORT, we also explored the effect of radiotherapy on prognosis. Surprisingly, we found that radiotherapy lengthened patients' survival rate time, while PORT did not elevate or even decreased patients' survival rate. One of the most common method for judging the prognosis of cancer is the nomogram. [18] In this retrospective study, we constructed an OS nomogram integrating available information such as age, tumor size, chemotherapy, radiation, surgery, T stage, grade, gender and marital status to predict OS. Previous scholars have constructed a variety of nomogram models for the prognosis of esophageal cancer. [19][20][21] Nonetheless, a nomogram for stage III esophageal cancer has not yet been constructed, which was the reason why we constructed this nomogram model. The Concordance Index, also known as the c-index, is adopted to evaluate the accuracy of the nomogram model. The c-index >0.7 is considered to have satisfactory predictive ability of nomogram model. [22] The c-index values of this OS nomogram was 0.663, indicating low discriminative ability. Hence, we did not validate the nomogram model. And the model can be employed as a reference tool for decision-making.
It's essential to discuss several limitations existing in this study. First and foremost, the treatment information in the SEER database is incomplete. The deficiency of crucial information such as radiation dose, chemotherapy dose, patient performance status, and radiation field hindered a more in-depth analysis on the prognostic value of PORT for stage III esophageal cancer. Likewise, although our study revealed that age, tumor size, surgery, T stage, grade, gender and marital status are independent risk factors, the shortage of relevant specific information made further analysis more difficult. Aside from that, the SEER database covers no more than a subset of the entire US patient population, which may not be representative of the entire population.

Conclusion
As evidently exhibited by the retrospective analysis, surgery can heighten OS and CSS, whereas PORT did not. Nonetheless, given the various limitations of this analysis, caution must be exercised before these findings are universally employed in clinical practice until more randomized trials confirm these results.